Outcomes of thoracic aortic interventions in Marfan syndrome in the state of Texas over 11 years

Abstract OBJECTIVES Marfan syndrome is a heritable connective tissue disorder with significant aortopathy and conveys substantial cardiovascular morbidity. This study characterizes the mortality and morbidities of thoracic aortic interventions (TAI) in the Marfan syndrome population in the state of Texas from 2009 to 2019. METHODS A retrospective review of the Texas Inpatient Discharge Dataset from 1 January 2009 to 31 December 2019. Discharges from acute care hospitals with a Marfan syndrome diagnosis by the International Classification of Diseases 9/10 codes and a procedure code for TAI were analysed utilizing descriptive, univariate and multivariable regression statistics. RESULTS There were 4641 Marfan syndrome discharges identified, of whom 644 (13.9%) underwent TAI. Thoracic or thoraco-abdominal aortic dissection or rupture was noted in 223 (34.6%). Thirty-three (5.1%) had a concomitant coronary artery intervention. There were 30 (4.7%) in-hospital mortalities, 126 (19.6%) diagnoses of acute renal failure (ARF), 52 (8.1%) had mechanical ventilation >96 h and the median length of stay was 10 [interquartile range (IQR) 7–16] days. After adjustment, concomitant coronary artery intervention was associated with in-hospital mortality [odds ratio (OR) 3.69 [IQR 1.15–11.90], P = 0.029] and ARF (OR 2.66 [IQR 1.19–5.94], P = 0.017). Aortic dissections/ruptures were associated with ARF (OR 1.73 [IQR 1.14–2.63], P = 0.010), ventilation >96 h (OR 2.19 [IQR 1.21–3.97], P = 0.010), and 15% longer length of stay (95% confidence interval 2.4–29.1%, P = 0.038). CONCLUSIONS TAI are frequent among the hospitalized Marfan Syndrome population. Concomitant coronary intervention is associated with increased risk of death and aortic dissections/ruptures are associated with increased morbidity. The high prevalence of aortic dissections/ruptures points to a potential target for improving imaging surveillance, adherence to treatment guidelines and preventative management of Marfan syndrome aortopathy.

CONCLUSIONS: TAI are frequent among the hospitalized Marfan Syndrome population. Concomitant coronary intervention is associated with increased risk of death and aortic dissections/ruptures are associated with increased morbidity. The high prevalence of aortic dissections/ruptures points to a potential target for improving imaging surveillance, adherence to treatment guidelines and preventative management of Marfan syndrome aortopathy.

INTRODUCTION
Marfan syndrome (MFS) is a connective tissue disorder associated with a defect in the fibrillin 1 protein [1]. It is most commonly inherited in an autosomal dominant fashion, but can be sporadic [1]. While affecting many different organ systems, it is associated with significant cardiovascular morbidity [2]. Dilation of the aortic root progressing to thoracic or thoraco-abdominal aortic dissection or rupture (TADR) was historically the leading cause of death in MFS [3]. Management of the thoracic aorta, therefore, has been researched extensively including: medical management [4][5][6], the Bentall procedure [7] versus aortic valvesparing procedures [8][9][10], timing of aortic root surgery based on dilation and/or increases in size [11,12], and open versus endovascular approaches [13][14][15]. To better track TADR outcomes, 2 registries were created: the International Registry of Acute Aortic Dissection [16] and the National Registry of Genetically Triggered Thoracic Aortic Aneurysms [17]. Both have yielded valuable insight into TADR, but they include other aortopathies, do not provide epidemiologic context such as MFS without TADR and do not capture settings in which prophylactic thoracic aortic interventions (TAI) may occur without TADR [8][9][10][11][12].
Despite increased awareness and research, in-hospital outcomes of TAI in the MFS population are limited. The goal of this study is to analyse contemporary outcomes of TAI in the MFS population in a large, statewide database over 11 years. The primary objective was to describe the rates of in-hospital mortality and complications such as acute renal failure (ARF), prolonged ventilation, temporary mechanical circulatory support (TMCS), including extracorporeal membranous oxygenation and longer length of stay (LOS), and evaluate factors associated with those complications.

Ethical statement
Institutional Review Board oversight was waived for this study as it consisted of publicly-curated, deidentified data.

Data source
Data originated from the Texas Inpatient Discharge Public Use File (TIDD) from 1 January 2009 to 31 December 2019. The TIDD is a deidentified, administrative database whose full details have been previously described [18,19]. It includes discharges from almost all hospitals in the state of Texas. Exemptions include those from hospitals in a county with a population less than 35,000, or those located in a county with a population more than 35,000 and with fewer than 100 licensed hospital beds and not located in an area that is delineated as an urbanized area by the United States Bureau of the Census. The TIDD provides an admitting, principal and up to 24 other diagnoses, and a principal procedure and up to 24 other procedures for each discharge. From 2009 to 2015q3, diagnoses and procedures were coded using the International Classification of Diseases (ICD)-9. Records from 2015q4 to 2019 were coded using the 10th Revision (ICD-10).

Study population
Discharges from acute care hospitalizations with MFS diagnoses (ICD codes 759.82, Q87.40-Q87.43) were identified. Demographics included sex, race, ethnicity, ageand insurance status. In the TIDD, patient age is categorized into 16 groups, which were collated into 0-9, 10-19, 20-34, 35-49, 50-64 and 65+years. Insurance status was grouped into Private, Uninsured, Medicare, Medicaid and Other. Clinical outcomes provided by the TIDD included in-hospital mortality and LOS. Discharges with incomplete demographic information were excluded from analysis.
TAI were identified by procedure codes indicating open surgical and endovascular interventions involving the thoracic aorta. Further diagnoses, procedures and outcomes identified using ICD-9/10 codes included: open versus endovascular approach, mitral valve interventions, aortic valve interventions and coronary artery interventions, hypertension, atherosclerosis, dyslipidaemia, diabetes mellitus, tobacco use, bicuspid aortic valves, ARF, TMCS and mechanical ventilation >96 h (MV96; Supplementary Material, Table S1). Additionally, TADR diagnoses grouped thoracic and thoraco-abdominal locations due to a lack of granularity afforded by ICD-9 codes. Hospitals were stratified into tertiles based on TAI volume.

Statistical analysis
Descriptive statistics were used for demographics, clinical characteristics and outcomes. Categorical variables are reported as n(%). LOS is reported in median [interquartile range (IQR)] days. Chi-squared and Fisher's exact test were utilized to analyse noncontinuous variables. Wilcoxon signed-rank test and Kruskal-Wallis test were used for non-normally distributed comparisons. Multivariable logistic and linear regressions were utilized for categorical and continuous variables, respectively. The models included clinically-relevant variables. There were at least 10 outcomes for each variable to reduce the risk of overfitting the models. All variables included were assessed for collinearity. All statistical tests were 2-tailed and a P-value < 0.05 was considered significant. All statistical analyses adhered to the Journal's statistical guidelines and were performed using R (20) and RStudio (RStudio, Boston, MA, USA) [20,21].

Population and characteristics
A total of 4641 MFS discharges were identified, out of which there were 644 (13.9%) discharges that underwent TAI, which comprised the study group (Table 1). Of the study group, a principal diagnosis of TADR was identified in 223 (34.6%) discharges. Other principle diagnoses, stratified by age group, are shown in Table 2. TADR or thoracic aortic aneurysms were the most common cardiovascular principal diagnosis in every age group except 0-9 years.

In-hospital mortality
In-hospital mortality occurred in 30 (4.7%) TAI discharges ( Table 3). The ages with the highest number of TAI in-hospital mortalities were 20-34 and 50-64 years with 9 (30%) each (Supplementary Material, Table S2). There was a decrease in in-hospital mortality rate as procedure volume increased by hospital tertile, but it did not amount to statistical significance (P = 0.718), nor did an individual assessment of the low-volume tertile compared to the high-volume tertile (P = 0.588; Fig. 2). Concomitant coronary artery interventions were associated with increased in-hospital mortality (n = 4, 13.3% vs n = 29, 4.7%, P = 0.037). After adjustment (Table 4), coronary artery interventions remained associated with in-hospital mortality fodds ratio 3.69 [95% confidence interval (CI) 1.15-11.90], P = 0.029g. There were no other associations identified.

DISCUSSION
We present contemporary outcomes of TAI performed in MFS patient discharges over the course of 11 years in a large, statewide database. To the authors' knowledge, this is the largest cohort of MFS hospitalizations reported, with 4641 MFS discharges identified undergoing 644 TAI [22]. Unlike other databases, such as National Registry of Genetically Triggered Thoracic Aortic Aneurysms or International Registry of Acute Aortic Dissection, this study addresses the TAI outcomes of all MFS hospitalizations, not restricted to those with TADR [16,17]. TAIs are a frequent occurrence, documented in 14% of MFS discharges and confer significant morbidity and an in-hospital mortality rate of 4.7%. This mortality rate is similar to previous reports on 30-day mortality for patients undergoing TAI in the general population, suggesting MFS may confer little additional risk of in-hospital mortality [23,24].

Age
Life expectancy in MFS has improved significantly from 30 years to 60+ years at experienced centres [3,25]. As this population ages, the potential need for TAI is substantial: 30% of all TAI occurred in discharges >50 years in this study. Age was associated with increased morbidity with increased ARF, MV96 and longer LOS among 35-49 and 50-64 year groups. Identifying those with increased risk of undergoing TAI and increased risk of morbidity and mortality post-TAI may help develop surveillance guidelines and strengthen focused care teams to improve their perioperative care.   Thoracic or thoraco-abdominal aortic dissections and rupture TADR is a well-known and devastating consequence of MFS, being a persistent source of mortality in MFS historically and contemporarily [3,26]. This study agrees that TADR persists as a significant problem, with 4.8% of all MFS discharges having a principal diagnosis of TADR and 34.6% of TAI occurring in the setting of TADR. As expected, TADR was associated with many adverse outcomes (ARF, MV96 and prolonged LOS). ARF is worrisome as a recent meta-analysis demonstrated acute kidney injury having increased risk of long-term mortality after cardiac surgery [27]. Preventing ARF among TADR should be a target for improving short-and-long-term morbidity. TADR had no associations with in-hospital mortality, but this is likely secondary to a mixture of acute, non-acute and historical TADR diagnoses, biasing these data towards the null. The high prevalence and considerable morbidity of TADR undergoing TAI indicate surveillance and primary prevention of TADR should continue to be a topic of study. Current guidelines recommend annual imaging of the aortic root in MFS, with increased frequency if aortic diameter >4.5 cm [28]. Given the high prevalence of TADR in this study cohort, and previous data suggesting aortic size >5.5 cm is not a good predictor of TADR, this suggests either greater adherence to guidelines is needed or revisiting surveillance measures is warranted [11,12,29].

Procedural considerations
Despite the potential complexity of adding mitral or aortic valvular interventions during TAI, they were not associated with  adverse outcomes. However, concomitant coronary artery interventions conferred 3.69-fold adjusted odds of in-hospital mortality-the only factor with this association-and 2.66-fold odds of ARF. The reason for increased risk with coronary interventions are unclear, especially without knowing the exact indications for coronary intervention. But given their substantial morbidity and mortality, TAI with coronary interventions should likely be performed in experienced centres. Endovascular approach was not associated with adverse outcomes in this study, which is consistent with recent reports [14]. However, there were no LOS benefits or decreased morbidity as one might expect with a less invasive approach. Some guidelines recommend against endovascular approaches for those with genetic aortopathy except in bail-out situations, though they were released after this study period concluded [15]. The endovascular approach was potentially reserved for sicker patients not amenable to open repair, therefore not conferring improvement in LOS. With no specific associations with adverse outcomes found in this study, it may be a viable treatment option, at least in the short term, and should be a target for continued inquiry. These results must be interpreted with caution as this study cannot interpret the long-term consequences where continued aortic dilation inherent in MFS aortopathy may distort the repair.
Hospital volume revealed no difference in outcomes aside from a longer LOS in the high-volume tertile after adjustment. Despite the in-hospital mortality rate declining as centre volume increased, it did not amount to statistical significance. This likely reflects the increased complexity at these higher-volume specialty centres, though the small number of hospitals performing the majority of TAI in this study may introduce centre-specific biases.

Limitations
This study has the limitations of using an administrative, discharge dataset. The sample is a hospitalized population, not the general MFS population. The unit of measure is discharges, not patients, so patients could be represented multiple times. Similarly, previous surgical and medical history are not able to be ascertained, including defined aspects of the Ghent criteria for MFS diagnosis [2]. Participating hospitals could misclassify or omit diagnoses or procedures, impacting analyses. ICD-9 codes lack granularity to distinguish thoracic and thoraco-abdominal location of aortic aneurysms or TADR; therefore, they were grouped together, which has significant implications on distinguishing between Stanford A vs B dissections. Similarly, it was impossible to discern between acute vs chronic vs historical TADR diagnoses. The absence of imaging to characterize aortic morphology precludes full understanding of aortopathy of those undergoing TAI. Finally, we do not know the temporal relationship between TAI and ICD-9/10 diagnosis codes; however, the median overall LOS was 10 (IQR 7-16) days and the median postoperative LOS was 9 (6-14) days, indicating that many diagnoses like MV96 likely occurred after the TAI.

CONCLUSIONS
Over the past decade, TAIs remain frequent in the hospitalized MFS population. TAI are associated with significant morbidity, and conferred an in-hospital mortality rate of 4.7%. Concomitant coronary artery interventions are independently associated with increased risk of death and TADR is associated with higher rates of important morbidities. The high prevalence of TADR is a potential target for improvement in imaging surveillance, adherence to treatment guidelines, and preventative management of aortopathy in the MFS population.

SUPPLEMENTARY MATERIAL
Supplementary material is available at ICVTS online.

ETHICAL STATEMENT
The Institutional Review Board for Dell Medical School waived the need for approval of this study as it consisted of publicly curated, deidentified data (IRB#2020-01-0052).